Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study.

BACKGROUND: Physical activity and exercise training are associated with a lower risk for coronary events. However, cross-sectional studies in middle-aged and older male athletes revealed increased coronary artery calcification (CAC) and atherosclerotic plaques, which were related to the amount and intensity of lifelong exercise. We examined the longitudinal relationship between exercise training characteristics and coronary atherosclerosis. METHODS: Middle-aged and older men from the MARC-1 (Measuring Athlete's Risk of Cardiovascular Events 1) study were invited for follow-up in MARC-2 (Measuring Athlete's Risk of Cardiovascular Events 2) study. The prevalence and severity of CAC and plaques were determined by coronary computed tomography angiography. The volume (metabolic equivalent of task [MET] hours/week) and intensity (moderate [3 to 6 MET hours/week]; vigorous [6 to 9 MET hours/week]; and very vigorous [≥9 MET hours/week]) of exercise training were quantified during follow-up. Linear and logistic regression analyses were performed to determine the association between exercise volume/intensity and markers of coronary atherosclerosis. RESULTS: We included 289 (age, 54 [50 to 60] years [median (Q1 to Q3)]) of the original 318 MARC-1 participants with a follow-up of 6.3±0.5 years (mean±SD). Participants exercised for 41 (25 to 57) MET hours/week during follow-up, of which 0% (0 to 19%) was at moderate intensity, 44% (0 to 84%) was at vigorous intensity, and 34% (0 to 80%) was at very vigorous intensity. Prevalence of CAC and the median CAC score increased from 52% to 71% and 1 (0 to 32) to 31 (0 to 132), respectively. Exercise volume during follow-up was not associated with changes in CAC or plaque. Vigorous intensity exercise (per 10% increase) was associated with a lesser increase in CAC score (ß, -0.05 [-0.09 to -0.01]; P=0.02), whereas very vigorous intensity exercise was associated with a greater increase in CAC score (ß, 0.05 [0.01 to 0.09] per 10%; P=0.01). Very vigorous exercise was also associated with increased odds of dichotomized plaque progression (adjusted odds ratio [aOR], 1.09 [1.01 to 1.18] per 10%; aOR, 2.04 [0.93 to 4.15] for highest versus lowest very vigorous intensity tertiles, respectively), and specifically with increased calcified plaques (aOR, 1.07 [1.00 to 1.15] per 10%; aOR, 2.09 [1.09 to 4.00] for highest versus lowest tertile, respectively). CONCLUSIONS: Exercise intensity but not volume was associated with progression of coronary atherosclerosis during 6-year follow-up. It is intriguing that very vigorous intensity exercise was associated with greater CAC and calcified plaque progression, whereas vigorous intensity exercise was associated with less CAC progression.

Exercise-induced cardiac troponin release in athletes with versus without coronary atherosclerosis.

The magnitude of exercise-induced cardiac troponin (cTn) elevations is dependent on cardiovascular health status, and previous studies have shown that occult coronary atherosclerosis is highly prevalent among amateur athletes. We tested the hypothesis that middle-aged and older athletes with coronary atherosclerosis demonstrate greater cTn elevations following a controlled endurance exercise test compared with healthy peers. We included 59 male athletes from the Measuring Athletes' Risk of Cardiovascular events 2 (MARC-2) study and stratified them as controls [coronary artery calcium score (CACS) = 0, n = 20], high CACS [≥300 Agatston units or ≥75th Multi-Ethnic Study of Atherosclerosis (MESA) percentile, n = 20] or significant stenosis (≥50% in any coronary artery, n = 19). Participants performed a cycling test with incremental workload until volitional exhaustion. Serial high-sensitivity cTn (hs-cTn) T and I concentrations were measured (baseline, after 30-min warm-up, and 0, 30, 60, 120, and 180 min postexercise). There were 58 participants (61 [58-69] yr) who completed the exercise test (76 ± 14 min) with a peak heart rate of 97.7 [94.8-101.8]% of their estimated maximum. Exercise duration and workload did not differ across groups. High-sensitivity cardiac troponin T (Hs-cTnT) and high-sensitivity cardiac troponin I (hs-cTnI) concentrations significantly increased (1.55 [1.33-2.14]-fold and 2.76 [1.89-3.86]-fold, respectively) over time, but patterns of cTn changes and the incidence of concentrations >99th percentile did not differ across groups. Serial sampling of hs-cTnT and hs-cTnI concentrations during and following an exhaustive endurance exercise test did not reveal differences in exercise-induced cTn release between athletes with versus without coronary atherosclerosis. These findings suggest that a high CACS or a >50% stenosis in any coronary artery does not aggravate exercise-induced cTn release in middle-aged and older athletes.NEW & NOTEWORTHY Exercise-induced cardiac troponin (cTn) release is considered to be dependent on cardiovascular health status. We tested whether athletes with coronary atherosclerosis demonstrate greater exercise-induced cTn release compared with healthy peers. Athletes with coronary atherosclerosis did not differ in cTn release following exercise compared with healthy peers. Our findings suggest that a high CACS or a >50% stenosis in any coronary artery does not aggravate exercise-induced cTn release in middle-aged and older athletes.

Hemodynamic Parameters in the Parent Arteries of Unruptured Intracranial Aneurysms Depend on Aneurysm Size and Are Different Compared to Contralateral Arteries: A 7 Tesla 4D Flow MRI Study.

BACKGROUND: Different Circle of Willis (CoW) variants have variable prevalences of aneurysm development, but the hemodynamic variation along the CoW and its relation to presence and size of unruptured intracranial aneurysms (UIAs) are not well known. PURPOSE: Gain insight into hemodynamic imaging markers of the CoW for UIA development by comparing these outcomes to the corresponding contralateral artery without an UIA using 4D flow magnetic resonance imaging (MRI). STUDY TYPE: Retrospective, cross-sectional study. SUBJECTS: Thirty-eight patients with an UIA, whereby 27 were women and a mean age of 62 years old. FIELD STRENGTH/SEQUENCE: Four-dimensional phase-contrast (PC) MRI with a 3D time-resolved velocity encoded gradient echo sequence at 7 T. ASSESSMENT: Hemodynamic parameters (blood flow, velocity pulsatility index [vPI], mean velocity, distensibility, and wall shear stress [peak systolic (WSSMAX ), and time-averaged (WSSMEAN )]) in the parent artery of the UIA were compared to the corresponding contralateral artery without an UIA and were related to UIA size. STATISTICAL TESTS: Paired t-tests and Pearson Correlation tests. The threshold for statistical significance was P < 0.05 (two-tailed). RESULTS: Blood flow, mean velocity, WSSMAX , and WSSMEAN were significantly higher, while vPI was lower, in the parent artery relative to contralateral artery. The WSSMAX of the parent artery significantly increased linearly while the WSSMEAN decreased linearly with increasing UIA size. CONCLUSIONS: Hemodynamic parameters and WSS differ between parent vessels of UIAs and corresponding contralateral vessels. WSS correlates with UIA size, supporting a potential hemodynamic role in aneurysm pathology. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Standardizing the estimation of ischemic regions can harmonize CT perfusion stroke imaging.

OBJECTIVES: We aimed to evaluate the real-world variation in CT perfusion (CTP) imaging protocols among stroke centers and to explore the potential for standardizing vendor software to harmonize CTP images. METHODS: Stroke centers participating in a nationwide multicenter healthcare evaluation were requested to share their CTP scan and processing protocol. The impact of these protocols on CTP imaging was assessed by analyzing data from an anthropomorphic phantom with center-specific vendor software with default settings from one of three vendors (A-C): IntelliSpace Portal, syngoVIA, and Vitrea. Additionally, standardized infarct maps were obtained using a logistic model. RESULTS: Eighteen scan protocols were studied, all varying in acquisition settings. Of these protocols, seven, eight, and three were analyzed with center-specific vendor software A, B, and C respectively. The perfusion maps were visually dissimilar between the vendor software but were relatively unaffected by the acquisition settings. The median error [interquartile range] of the infarct core volumes (mL) estimated by the vendor software was - 2.5 [6.5] (A)/ - 18.2 [1.2] (B)/ - 8.0 [1.4] (C) when compared to the ground truth of the phantom (where a positive error indicates overestimation). Taken together, the median error [interquartile range] of the infarct core volumes (mL) was - 8.2 [14.6] before standardization and - 3.1 [2.5] after standardization. CONCLUSIONS: CTP imaging protocols varied substantially across different stroke centers, with the perfusion software being the primary source of differences in CTP images. Standardizing the estimation of ischemic regions harmonized these CTP images to a degree. CLINICAL RELEVANCE STATEMENT: The center that a stroke patient is admitted to can influence the patient's diagnosis extensively. Standardizing vendor software for CT perfusion imaging can improve the consistency and accuracy of results, enabling a more reliable diagnosis and treatment decision. KEY POINTS: • CT perfusion imaging is widely used for stroke evaluation, but variation in the acquisition and processing protocols between centers could cause varying patient diagnoses. • Variation in CT perfusion imaging mainly arises from differences in vendor software rather than acquisition settings, but these differences can be reconciled by standardizing the estimation of ischemic regions. • Standardizing the estimation of ischemic regions can improve CT perfusion imaging for stroke evaluation by facilitating reliable evaluations independent of the admission center.

The influence of motion-compensated reconstruction on coronary artery analysis for a dual-layer detector CT system: a dynamic phantom study.

OBJECTIVES: Cardiac motion artifacts hinder the assessment of coronary arteries in coronary computed tomography angiography (CCTA). We investigated the impact of motion compensation reconstruction (MCR) on motion artifacts in CCTA at various heart rates (HR) using a dynamic phantom. MATERIALS AND METHODS: An artificial hollow coronary artery (5-mm diameter lumen) filled with iodinated contrast agent (400 HU at 120 kVp), positioned centrally in an anthropomorphic chest phantom, was scanned using a dual-layer spectral detector CT. The artery was translated at constant horizontal velocities (0-80 mm/s, increment of 10 mm/s). For each velocity, five CCTA scans were repeated using a clinical protocol. Motion artifacts were quantified using the in-plane motion area. Regression analysis was performed to calculate the reduction in motion artifacts provided by MCR, by division of the slopes of non-MCR and MCR fitted lines. RESULTS: Reference mean (95% confidence interval) motion artifact area was 24.9 mm2 (23.8, 26.0). Without MCR, motion artifact areas for velocities exceeding 20 mm/s were significantly larger (up to 57.2 mm2 (40.1, 74.2)) than the reference. With MCR, no significant differences compared to the reference were shown for all velocities, except for 70 mm/s (29.0 mm2 (27.0, 31.0)). The slopes of the fitted data were 0.44 and 0.04 for standard and MCR reconstructions, respectively, resulting in an 11-time motion artifact reduction. CONCLUSION: MCR may improve CCTA assessment in patients by reducing coronary artery motion artifacts, especially in those with elevated HR who cannot receive beta blockers or do not attain the targeted HR. CLINICAL RELEVANCE STATEMENT: This vendor-specific motion compensation reconstruction may improve coronary computed tomography angiography assessment in patients by reduction of coronary artery motion artifacts, especially in those with elevated various heart rates (HR) who cannot receive beta blockers or do not attain the targeted HR. KEY POINTS: • Motion artifacts are known to hinder the assessment of coronary arteries on coronary CT angiography (CCTA), leading to more non-diagnostic scans. • This dynamic phantom study shows that motion compensation reconstruction (MCR) reduces motion artifacts at various velocities, which may help to decrease the number of non-diagnostic scans. • MCR in this study showed to reduce motion artifacts 11-fold.

Diagnostic value of late gadolinium enhancement at cardiovascular magnetic resonance to distinguish arrhythmogenic right ventricular cardiomyopathy from differentials.

BACKGROUND: While late gadolinium enhancement (LGE) is proposed as a diagnostic criterion for arrhythmogenic right ventricular cardiomyopathy (ARVC), the potential of LGE to distinguish ARVC from differentials remains unknown. We aimed to assess the diagnostic value of LGE for ARVC diagnosis. METHODS: We included 132 subjects (60% male, 47 ± 11 years) who had undergone cardiac magnetic resonance imaging with LGE assessment for ARVC or ARVC differentials. ARVC was diagnosed as per 2010 Task Force Criteria (n = 55). ARVC differentials consisted of familial/genetic dilated cardiomyopathy (n = 25), myocarditis (n = 13), sarcoidosis (n = 20), and amyloidosis (n = 19). The diagnosis of all differentials was based on the most current standard of reference. The presence of LGE was evaluated using a 7-segment right ventricle (RV) and 17-segment left ventricle (LV) model. Subsequently, we assessed LGE patterns for every patient individually for fulfilling LV- and/or RV-LGE per Padua criteria, independent of their clinical diagnosis (i.e. phenotype). Diagnostic values were analyzed using sensitivity and specificity for any RV-LGE, any LV-LGE, RV-LGE per Padua criteria, and prevalence graphs for LV-LGE per Padua criteria. The optimal integration of LGE for ARVC diagnosis was determined using classification and regression tree analysis. RESULTS: One-third (38%) of ARVC patients had RV-LGE, while half (51%) had LV-LGE. RV-LGE was less frequently observed in ARVC vs non-ARVC patients (38% vs 58%, p = 0.034) leading to a poor discriminatory potential (any RV-LGE: sensitivity 38%, specificity 42%; RV-LGE per Padua criteria: sensitivity 36%, specificity 44%). Compared to ARVC patients, non-ARVC patients more often had LV-LGE (91% vs 51%, p < 0.001) which was also more globally distributed (median 9 [interquartile range (IQR): 3-13] vs 0 [IQR: 0-3] segments, p < 0.001). The absence of anteroseptal and absence of extensive (≥5 segments) mid-myocardial LV-LGE, and absence of moderate (≥2 segments) mid-myocardial LV-LGE predicted ARVC with good diagnostic performance (sensitivity 93%, specificity 78%). CONCLUSION: LGE is often present in ARVC differentials and may lead to false positive diagnoses when used without knowledge of LGE patterns. Moderate RV-LGE without anteroseptal and mid-myocardial LV-LGE is typically observed in ARVC.

Computed tomography and coronary artery calcium score for screening of coronary artery disease and cardiovascular risk management in asymptomatic individuals.

Several risk prediction models exist to predict atherosclerotic cardiovascular disease in asymptomatic individuals, but systematic reviews have generally found these models to be of limited utility. The coronary artery calcium score (CACS) offers an improvement in risk prediction, yet its role remains contentious. Notably, its negative predictive value has a high ability to rule out clinically relevant atherosclerotic cardiovascular disease. Nonetheless, CACS 0 does not permanently reclassify to a lower cardiovascular risk and periodic reassessment every 5 to 10 years remains necessary. Conversely, elevated CACS (> 100 or > 75th percentile adjusted for age, sex and ethnicity) can reclassify intermediate-risk individuals to a high risk, benefiting from preventive medication. The forthcoming update to the Dutch cardiovascular risk management guideline intends to re-position CACS for cardiovascular risk assessment as such in asymptomatic individuals. Beyond CACS as a single number, several guidelines recommend coronary CT angiography (CCTA), which provides additional information about luminal stenosis and (high-risk) plaque composition, as the first choice of test in symptomatic patients and high-risk patients. Ongoing randomised studies will have to determine the value of atherosclerosis evaluation with CCTA for primary prevention in asymptomatic individuals.

Detection of Cardioembolic Sources With Nongated Cardiac Computed Tomography Angiography in Acute Stroke: Results From the ENCLOSE Study.

BACKGROUND: Identifying cardioembolic sources in patients with acute ischemic stroke is important for the choice of secondary prevention strategies. We prospectively investigated the yield of admission (spectral) nongated cardiac computed tomography angiography (CTA) to detect cardioembolic sources in stroke. METHODS: Participants of the ENCLOSE study (Improved Prediction of Recurrent Stroke and Detection of Small Volume Stroke) with transient ischemic attack or acute ischemic stroke with assessable nongated head-to-heart CTA at the University Medical Center Utrecht were included between June 2017 and March 2022. The presence of cardiac thrombus on cardiac CTA was based on a Likert scale and dichotomized into certainly or probably absent versus possibly, probably, or certainly present. The diagnostic certainty of cardiac thrombus was evaluated again on spectral computed tomography reconstructions. The likelihood of a cardioembolic source was determined post hoc by an expert panel in patients with cardiac thrombus on CTA. Parametric and nonparametric tests were used to compare the outcome groups. RESULTS: Forty four (12%) of 370 included patients had a cardiac thrombus on admission CTA: 35 (9%) in the left atrial appendage and 14 (4%) in the left ventricle. Patients with cardiac thrombus had more severe strokes (median National Institutes of Health Stroke Scale score, 10 versus 4; P=0.006), had higher clot burden (median clot burden score, 9 versus 10; P=0.004), and underwent endovascular treatment more often (43% versus 20%; P<0.001) than patients without cardiac thrombus. Left atrial appendage thrombus was present in 28% and 6% of the patients with and without atrial fibrillation, respectively (P<0.001). The diagnostic certainty for left atrial appendage thrombus was higher for spectral iodine maps compared with the conventional CTA (P<0.001). The presence of cardiac thrombus on CTA increased the likelihood of a cardioembolic source according to the expert panel (P<0.001). CONCLUSIONS: Extending the stroke CTA to cover the heart increases the chance of detecting cardiac thrombi and helps to identify cardioembolic sources in the acute stage of ischemic stroke with more certainty. Spectral iodine maps provide additional value for detecting left atrial appendage thrombus. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04019483.

Cardiac radiology in Europe: status and vision by the European Society of Cardiovascular Radiology (ESCR) and the European Society of Radiology (ESR).

Cardiac computed tomography (CT) and cardiac magnetic resonance imaging (MRI) are routine radiological examinations for diagnosis and prognosis of cardiac disease. The expected growth in cardiac radiology in the coming years will exceed the current scanner capacity and trained workforce. The European Society of Cardiovascular Radiology (ESCR) focuses on supporting and strengthening the role of cardiac cross-sectional imaging in Europe from a multi-modality perspective. Together with the European Society of Radiology (ESR), the ESCR has taken the initiative to describe the current status of, a vision for, and the required activities in cardiac radiology to sustain, increase and optimize the quality and availability of cardiac imaging and experienced radiologists across Europe. KEY POINTS: • Providing adequate availability for performing and interpreting cardiac CT and MRI is essential, especially with expanding indications. • The radiologist has a central role in non-invasive cardiac imaging examinations which encompasses the entire process from selecting the best modality to answer the referring physician's clinical question to long-term image storage. • Optimal radiological education and training, knowledge of the imaging process, regular updating of diagnostic standards, and close collaboration with colleagues from other specialties are essential.

State-of-the-art CT and MR imaging and assessment of atherosclerotic carotid artery disease: the reporting-a consensus document by the European Society of Cardiovascular Radiology (ESCR).

The European Society of Cardiovascular Radiology (ESCR) is the European specialist society of cardiac and vascular imaging. This society's highest priority is the continuous improvement, development, and standardization of education, training, and best medical practice, based on experience and evidence. The present intra-society consensus is based on the existing scientific evidence and on the individual experience of the members of the ESCR writing group on carotid diseases, the members of the ESCR guidelines committee, and the members of the executive committee of the ESCR. The recommendations published herein reflect the evidence-based society opinion of ESCR. The purpose of this second document is to discuss suggestions for standardized reporting based on the accompanying consensus document part I. KEY POINTS: • CT and MR imaging-based evaluation of carotid artery disease provides essential information for risk stratification and prediction of stroke. • The information in the report must cover vessel morphology, description of stenosis, and plaque imaging features. • A structured approach to reporting ensures that all essential information is delivered in a standardized and consistent way to the referring clinician.

State-of-the-art CT and MR imaging and assessment of atherosclerotic carotid artery disease: standardization of scanning protocols and measurements-a consensus document by the European Society of Cardiovascular Radiology (ESCR).

The European Society of Cardiovascular Radiology (ESCR) is the European specialist society of cardiac and vascular imaging. This society's highest priority is the continuous improvement, development, and standardization of education, training, and best medical practice, based on experience and evidence. The present intra-society consensus is based on the existing scientific evidence and on the individual experience of the members of the ESCR writing group on carotid diseases, the members of the ESCR guidelines committee, and the members of the executive committee of the ESCR. The recommendations published herein reflect the evidence-based society opinion of ESCR. We have produced a twin-papers consensus, indicated through the documents as respectively "Part I" and "Part II." The first document (Part I) begins with a discussion of features, role, indications, and evidence for CT and MR imaging-based diagnosis of carotid artery disease for risk stratification and prediction of stroke (Section I). It then provides an extensive overview and insight into imaging-derived biomarkers and their potential use in risk stratification (Section II). Finally, detailed recommendations about optimized imaging technique and imaging strategies are summarized (Section III). The second part of this consensus paper (Part II) is focused on structured reporting of carotid imaging studies with CT/MR. KEY POINTS: • CT and MR imaging-based evaluation of carotid artery disease provides essential information for risk stratification and prediction of stroke. • Imaging-derived biomarkers and their potential use in risk stratification are evolving; their correct interpretation and use in clinical practice must be well-understood. • A correct imaging strategy and scan protocol will produce the best possible results for disease evaluation.

Body surface potential mapping detects early disease onset in plakophilin-2-pathogenic variant carriers.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive inherited cardiac disease. Early detection of disease and risk stratification remain challenging due to heterogeneous phenotypic expression. The standard configuration of the 12 lead electrocardiogram (ECG) might be insensitive to identify subtle ECG abnormalities. We hypothesized that body surface potential mapping (BSPM) may be more sensitive to detect subtle ECG abnormalities. METHODS AND RESULTS: We obtained 67 electrode BSPM in plakophilin-2 (PKP2)-pathogenic variant carriers and control subjects. Subject-specific computed tomography/magnetic resonance imaging based models of the heart/torso and electrode positions were created. Cardiac activation and recovery patterns were visualized with QRS- and STT-isopotential map series on subject-specific geometries to relate QRS-/STT-patterns to cardiac anatomy and electrode positions. To detect early signs of functional/structural heart disease, we also obtained right ventricular (RV) echocardiographic deformation imaging. Body surface potential mapping was obtained in 25 controls and 42 PKP2-pathogenic variant carriers. We identified five distinct abnormal QRS-patterns and four distinct abnormal STT-patterns in the isopotential map series of 31/42 variant carriers. Of these 31 variant carriers, 17 showed no depolarization or repolarization abnormalities in the 12 lead ECG. Of the 19 pre-clinical variant carriers, 12 had normal RV-deformation patterns, while 7/12 showed abnormal QRS- and/or STT-patterns. CONCLUSION: Assessing depolarization and repolarization by BSPM may help in the quest for early detection of disease in variant carriers since abnormal QRS- and/or STT-patterns were found in variant carriers with a normal 12 lead ECG. Because electrical abnormalities were observed in subjects with normal RV-deformation patterns, we hypothesize that electrical abnormalities develop prior to functional/structural abnormalities in ARVC.

Reliability of velocity pulsatility in small vessels on 3Tesla MRI in the basal ganglia: a test-retest study.

OBJECTIVE: Recent work showed the feasibility of measuring velocity pulsatility in the perforating arteries at the level of the BG using 3T MRI. However, test-retest measurements have not been performed, yet. This study assessed the test-retest reliability of 3T MRI blood flow velocity measurements in perforating arteries in the BG. MATERIALS AND METHODS: Two-dimensional phase-contrast cardiac gated (2D-PC) images were acquired for 35 healthy controls and repeated with and without repositioning. 2D-PC images were processed and analyzed, to assess the number of detected perforating arteries (Ndetected), mean blood flow velocity (Vmean), and velocity pulsatility index (vPI). Paired t-tests and Bland-Altman plots were used to compare variance in outcome parameters with and without repositioning, and limits of agreement (LoA) were calculated. RESULTS: The LoA was smallest for Vmean (35%) and highest for vPI (79%). Test-retest reliability was similar with and without repositioning of the subject. DISCUSSION: We found similar LoA with and without repositioning indicating that the measurement uncertainty is dominated by scanner and physiological noise, rather than by planning. This enables to study hemodynamic parameters in perforating arteries at clinically available scanners, provided sufficiently large sample sizes are used to mitigate the contribution of scanner- and physiological noise.

Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy: a translational study.

AIMS: Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls. METHODS AND RESULTS: Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls. CONCLUSIONS: We speculate that exercise challenges a cardiomyocyte "desmosomal reserve" which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy.

Does the Internal Carotid Artery Attenuate Blood-Flow Pulsatility in Small Vessel Disease? A 7 T 4D-Flow MRI Study.

BACKGROUND: Increased cerebral blood-flow pulsatility is associated with cerebral small vessel disease (cSVD). Reduced pulsatility attenuation over the internal carotid artery (ICA) could be a contributing factor to the development of cSVD and could be associated with intracranial ICA calcification (iICAC). PURPOSE: To compare pulsatility, pulsatility attenuation, and distensibility along the ICA between patients with cSVD and controls and to assess the association between iICAC and pulsatility and distensibility. STUDY TYPE: Retrospective, explorative cross-sectional study. SUBJECTS: A total of 17 patients with cSVD, manifested as lacunar infarcts or deep intracerebral hemorrhage, and 17 age- and sex-matched controls. FIELD STRENGTH/SEQUENCE: Three-dimensional (3D) T1-weighted gradient echo imaging and 4D phase-contrast (PC) MRI with a 3D time-resolved velocity encoded gradient echo sequence at 7 T. ASSESSMENT: Blood-flow velocity pulsatility index (vPI) and arterial distensibility were calculated for seven ICA segments (C1-C7). iICAC presence and volume were determined from available brain CT scans (acquired as part of standard clinical care) in patients with cSVD. STATISTICAL TESTS: Independent t-tests and linear mixed models. The threshold for statistically significance was P < 0.05 (two tailed). RESULTS: The cSVD group showed significantly higher ICA vPI and significantly lower distensibility compared to controls. Controls showed significant attenuation of vPI over the carotid siphon (-4.9% ± 3.6%). In contrast, patients with cSVD showed no attenuation, but a significant increase of vPI (+6.5% ± 3.1%). iICAC presence and volume correlated positively with vPI (r = 0.578) in patients with cSVD and negatively with distensibility (r = -0.386). CONCLUSION: Decreased distensibility and reduced pulsatility attenuation are associated with increased iICAC and may contribute to cSVD. Confirmation in a larger prospective study is required. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Probability maps classify ischemic stroke regions more accurately than CT perfusion summary maps.

OBJECTIVES: To compare single parameter thresholding with multivariable probabilistic classification of ischemic stroke regions in the analysis of computed tomography perfusion (CTP) parameter maps. METHODS: Patients were included from two multicenter trials and were divided into two groups based on their modified arterial occlusive lesion grade. CTP parameter maps were generated with three methods-a commercial method (ISP), block-circulant singular value decomposition (bSVD), and non-linear regression (NLR). Follow-up non-contrast CT defined the follow-up infarct region. Conventional thresholds for individual parameter maps were established with a receiver operating characteristic curve analysis. Probabilistic classification was carried out with a logistic regression model combining the available CTP parameters into a single probability. RESULTS: A total of 225 CTP data sets were included, divided into a group of 166 patients with successful recanalization and 59 with persistent occlusion. The precision and recall of the CTP parameters were lower individually than when combined into a probability. The median difference [interquartile range] in mL between the estimated and follow-up infarct volume was 29/23/23 [52/50/52] (ISP/bSVD/NLR) for conventional thresholding and was 4/6/11 [31/25/30] (ISP/bSVD/NLR) for the probabilistic classification. CONCLUSIONS: Multivariable probability maps outperform thresholded CTP parameter maps in estimating the infarct lesion as observed on follow-up non-contrast CT. A multivariable probabilistic approach may harmonize the classification of ischemic stroke regions. KEY POINTS: • Combining CTP parameters with a logistic regression model increases the precision and recall in estimating ischemic stroke regions. • Volumes following from a probabilistic analysis predict follow-up infarct volumes better than volumes following from a threshold-based analysis. • A multivariable probabilistic approach may harmonize the classification of ischemic stroke regions.

Imaging markers of intracranial aneurysm development: A systematic review.

BACKGROUND: Imaging markers of intracranial aneurysm (IA) development are not well established. PURPOSE: To provide an overview of imaging markers of IA development. METHODS: A systematic search of PubMed and Embase up to December 1st 2020 using predefined criteria. Thirty-six studies met our inclusion criteria. We performed a quantitative summary of the included studies. RESULTS: We found converging evidence for A1 segment asymmetry as an anatomical marker of anterior communicating artery (Acom) aneurysm development, and moderate evidence for several other markers. No hemodynamic markers yielded converging or moderate evidence. There was large heterogeneity across studies, especially in the definitions of imaging markers and study outcomes used. Due to the poor methodological quality of many studies and unavailability of effect sizes or crude data to calculate effect sizes, a formal meta-analysis was not possible. CONCLUSIONS: We only identified A1 segment asymmetry as an imaging marker of Acom aneurysm development with converging evidence. A meta-analysis was not possible due to the heterogeneity of marker definitions and outcomes used, and poor methodological quality of many studies. Future studies should use robust study designs and uniformly defined imaging markers and outcome measures.

Exercise and Coronary Atherosclerosis: Observations, Explanations, Relevance, and Clinical Management.

Physical activity and exercise training are effective strategies for reducing the risk of cardiovascular events, but multiple studies have reported an increased prevalence of coronary atherosclerosis, usually measured as coronary artery calcification, among athletes who are middle-aged and older. Our review of the medical literature demonstrates that the prevalence of coronary artery calcification and atherosclerotic plaques, which are strong predictors for future cardiovascular morbidity and mortality, was higher in athletes compared with controls, and was higher in the most active athletes compared with less active athletes. However, analysis of plaque morphology revealed fewer mixed plaques and more often only calcified plaques among athletes, suggesting a more benign composition of atherosclerotic plaques. This review describes the effects of physical activity and exercise training on coronary atherosclerosis in athletes who are middle-aged and older and aims to contribute to the understanding of the potential adverse effects of the highest doses of exercise training on the coronary arteries. For this purpose, we will review the association between exercise and coronary atherosclerosis measured using computed tomography, discuss the potential underlying mechanisms for exercise-induced coronary atherosclerosis, determine the clinical relevance of coronary atherosclerosis in middle-aged athletes and describe strategies for the clinical management of athletes with coronary atherosclerosis to guide physicians in clinical decision making and treatment of athletes with elevated coronary artery calcification scores.

Comparing methods of detecting and segmenting unruptured intracranial aneurysms on TOF-MRAS: The ADAM challenge.

Accurate detection and quantification of unruptured intracranial aneurysms (UIAs) is important for rupture risk assessment and to allow an informed treatment decision to be made. Currently, 2D manual measures used to assess UIAs on Time-of-Flight magnetic resonance angiographies (TOF-MRAs) lack 3D information and there is substantial inter-observer variability for both aneurysm detection and assessment of aneurysm size and growth. 3D measures could be helpful to improve aneurysm detection and quantification but are time-consuming and would therefore benefit from a reliable automatic UIA detection and segmentation method. The Aneurysm Detection and segMentation (ADAM) challenge was organised in which methods for automatic UIA detection and segmentation were developed and submitted to be evaluated on a diverse clinical TOF-MRA dataset. A training set (113 cases with a total of 129 UIAs) was released, each case including a TOF-MRA, a structural MR image (T1, T2 or FLAIR), annotation of any present UIA(s) and the centre voxel of the UIA(s). A test set of 141 cases (with 153 UIAs) was used for evaluation. Two tasks were proposed: (1) detection and (2) segmentation of UIAs on TOF-MRAs. Teams developed and submitted containerised methods to be evaluated on the test set. Task 1 was evaluated using metrics of sensitivity and false positive count. Task 2 was evaluated using dice similarity coefficient, modified hausdorff distance (95th percentile) and volumetric similarity. For each task, a ranking was made based on the average of the metrics. In total, eleven teams participated in task 1 and nine of those teams participated in task 2. Task 1 was won by a method specifically designed for the detection task (i.e. not participating in task 2). Based on segmentation metrics, the top two methods for task 2 performed statistically significantly better than all other methods. The detection performance of the top-ranking methods was comparable to visual inspection for larger aneurysms. Segmentation performance of the top ranking method, after selection of true UIAs, was similar to interobserver performance. The ADAM challenge remains open for future submissions and improved submissions, with a live leaderboard to provide benchmarking for method developments at https://adam.isi.uu.nl/.

Variation in arterial input function in a large multicenter computed tomography perfusion study.

OBJECTIVES: To report the variation in computed tomography perfusion (CTP) arterial input function (AIF) in a multicenter stroke study and to assess the impact this has on CTP results. METHODS: CTP datasets from 14 different centers were included from the DUtch acute STroke (DUST) study. The AIF was taken as a direct measure to characterize contrast bolus injection. Statistical analysis was applied to evaluate differences in amplitude, area under the curve (AUC), bolus arrival time (BAT), and time to peak (TTP). To assess the clinical relevance of differences in AIF, CTP acquisitions were simulated with a realistic anthropomorphic digital phantom. Perfusion parameters were extracted by CTP analysis using commercial software (IntelliSpace Portal (ISP), version 10.1) as well as an in-house method based on block-circulant singular value decomposition (bSVD). RESULTS: A total of 1422 CTP datasets were included, ranging from 6 to 322 included patients per center. The measured values of the parameters used to characterize the AIF differed significantly with approximate interquartile ranges of 200-750 HU for the amplitude, 2500-10,000 HU·s for the AUC, 0-17 s for the BAT, and 10-26 s for the TTP. Mean infarct volumes of the phantom were significantly different between centers for both methods of perfusion analysis. CONCLUSIONS: Although guidelines for the acquisition protocol are often provided for centers participating in a multicenter study, contrast medium injection protocols still vary. The resulting volumetric differences in infarct core and penumbra may impact clinical decision making in stroke diagnosis. KEY POINTS: • The contrast medium injection protocol may be different between stroke centers participating in a harmonized multicenter study. • The contrast medium injection protocol influences the results of X-ray computed tomography perfusion imaging. • The contrast medium injection protocol can impact stroke diagnosis and patient selection for treatment.